A randomized controlled pilot trial of anakinra for hemodialysis inflammation
Authors: Laura M. Dember, Adriana Hung, Rajnish Mehrotra, Jesse Y. Hsu, Dominic S. Raj, David M. Charytan, Finnian R. Mc Causland, Renu Regunathan-Shenk, J. Richard Landis, Paul L. Kimmel, Alan S. Kliger, Jonathan Himmelfarb, T. Alp Ikizler
Journal: Kidney International (2022)

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients. Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients. The mortality rate for patients undergoing maintenance hemodialysis is unacceptably high with most of the deaths due to cardiovascular disease, infection, or protein-energy wasting.1Himmelfarb J. Ikizler T.A. Hemodialysis. N Engl J Med. 2010; 363: 1833-1845Crossref PubMed Scopus (253) Google Scholar Randomized controlled trials targeting traditional and nontraditional cardiovascular risk factors have had a minimal impact on survival in this population. Inflammatory biomarkers are predictors of cardiovascular events and mortality in the hemodialysis population,2Kimmel P.L. Phillips T.M. Simmens S.J. et al.Immunologic function and survival in hemodialysis patients.Kidney Int. 1998; 54: 236-244Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar, 3Stenvinkel P. Barany P. Heimburger O. et al.Mortality, malnutrition, and atherosclerosis in ESRD: what is the role of interleukin-6?.Kidney Int Suppl. 2002; : 103-108Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 4Stenvinkel P. Heimburger O. Jogestrand T. Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity.Am J Kidney Dis. 2002; 39: 274-282Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar and inflammation has been implicated in the pathogenesis of atherosclerosis and protein-energy wasting.5Ross R. Atherosclerosis—an inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (19530) Google Scholar, 6Ikizler T.A. Nutrition, inflammation and chronic kidney disease.Curr Opin Nephrol Hypertens. 2008; 17: 162-167Crossref PubMed Scopus (57) Google Scholar, 7Amdur R.L. Feldman H.I. Dominic E.A. et al.Use of measures of inflammation and kidney function for prediction of atherosclerotic vascular disease events and death in patients with CKD: findings from the CRIC study.Am J Kidney Dis. 2019; 73: 344-353Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 8Ikizler T.A. Burrowes J.D. Byham-Gray L.D. et al.KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update.Am J Kidney Dis. 2020; 76: S1-S107Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar Suppressing inflammation with anticytokine therapy has been proposed to reduce inflammation-associated morbidity, but there are few studies using this strategy for patients receiving maintenance hemodialysis. High levels of interleukin-1β (IL-1β), a highly active proinflammatory cytokine, and its naturally occurring receptor antagonist (IL-1ra) have been well documented in kidney failure.2Kimmel P.L. Phillips T.M. Simmens S.J. et al.Immunologic function and survival in hemodialysis patients.Kidney Int. 1998; 54: 236-244Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar,9Descamps-Latscha B. Herbelin A. Nguyen A.T. et al.Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis. Relationships with activation markers of T cells, B cells, and monocytes.J Immunol. 1995; 154: 882-892Crossref PubMed Google Scholar,10Pereira B.J. Shapiro L. King A.J. et al.Plasma levels of IL-1 beta, TNF alpha and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients.Kidney Int. 1994; 45: 890-896Abstract Full Text PDF PubMed Scopus (363) Google Scholar Treatment with IL-1ra is an established approach for rheumatoid arthritis, autoinflammatory conditions, and gout,11Bresnihan B. Alvaro-Gracia J.M. Cobby M. et al.Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist.Arthritis Rheum. 1998; 41: 2196-2204Crossref PubMed Scopus (941) Google Scholar, 12Hoffman H.M. Rosengren S. Boyle D.L. et al.Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist.Lancet. 2004; 364: 1779-1785Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar, 13Hawkins P.N. Lachmann H.J. McDermott M.F. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome.N Engl J Med. 2003; 348: 2583-2584Crossref PubMed Scopus (402) Google Scholar, 14Saag K.G. Khanna P.P. Keenan R.T. et al.A randomized, phase II study evaluating the efficacy and safety of anakinra in the treatment of gout flares.Arthritis Rheumatol. 2021; 73: 1533-1542Crossref PubMed Scopus (25) Google Scholar but neither the safety nor efficacy of targeting IL-1 for chronic inflammation in the setting of hemodialysis has been established. We performed a pilot, double-blind, randomized, placebo-controlled trial to evaluate the safety and tolerability of anakinra, an IL-1ra, for patients receiving maintenance hemodialysis, and to explore its efficacy on biochemical and patient-reported outcomes. An important goal of this early phase study was to assess the feasibility of a subsequent trial powered to assess efficacy on clinical outcomes. ACTION was a parallel group, double-blind, randomized, placebo-controlled pilot trial to evaluate safety, tolerability, and feasibility, and explore the efficacy of anakinra among hemodialysis patients (NCT03141983). The full protocol is available in the Supplementary Materials. Participants were enrolled from dialysis units affiliated with Brigham and Women's Hospital, Boston, Massachusetts; George Washington University, Washington, DC; University of Washington, Seattle, Washington; and Vanderbilt University Medical Center, Nashville, Tennessee. An external Data and Safety Monitoring Board, appointed by the National Institute of Diabetes and Digestive and Kidney Diseases, approved the protocol and reviewed progress, quality, and safety during trial conduct. The institutional review boards affiliated with the enrolling centers and with the Data Coordinating Center (University of Pennsylvania) approved the protocol. All participants provided written informed consent. The inclusion criteria included age 18–85 years, treatment with hemodialysis for ≥6 months, and negative testing for human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis C antibody or documented hepatitis C viral clearance following direct antiviral therapy, and tuberculosis using an interferon gamma release assay. High-sensitivity C-reactive protein (hsCRP) concentration had to be ≥2.0 mg/l at 2 screening visits, with the second occurring ≤10 days before randomization. In the original protocol, the eligibility threshold for hsCRP was ≥3.0 mg/l with a stipulation that the threshold could be lowered to ≥2.0 mg/l if the hsCRP threshold was an important barrier to enrollment. This prespecified change to the hsCRP eligibility threshold was implemented on May 23, 2018, after 20 participants had been randomized. Women of child-bearing potential were required to have a negative serum pregnancy test and use an approved method of birth control until 4 weeks after treatment with the study drug. The major exclusion criteria were current or anticipated use of a hemodialysis central venous catheter, acute bacterial infection within 60 days before screening unless treated with antibiotics and resolved, chronic bacterial infection, hospitalization within 30 days unless for a vascular access procedure, malignancy within 5 years other than basal or squamous cell carcinoma of the skin, cirrhosis, use of an immunosuppressive drug within the past 3 months, receipt of a live vaccine within the past 3 months, absolute neutrophil count <2500 cells/mm3, and platelet count <100,000 cells/mm3. The neutrophil and platelet counts were measured from blood obtained at a screening visit. Participants were randomized to placebo or anakinra in a 1:1 distribution using random permuted blocks of 4 or 6, with stratification by the presence or absence of diabetes and enrolling center. Randomization was performed via a web-based system, and participants and all research personnel were masked to treatment assignment. Study drug (anakinra or placebo) was administered via the hemodialysis blood circuit over 1 minute during the last 30 minutes of the dialysis session, 3 times per week for 24 weeks. This dosing approach was based on a pharmacokinetic study indicating that in hemodialysis the same dose can be used for intravenous and subcutaneous administration routes.15Yang B.B. Baughman S. Sullivan J.T. Pharmacokinetics of anakinra in subjects with different levels of renal function.Clin Pharmacol Ther. 2003; 74: 85-94Crossref PubMed Scopus (95) Google Scholar After the study drug treatment period, participants were followed for an additional 24 weeks for further assessment of safety. Participants who discontinued study drug early were followed for the full 48 weeks. Temporary discontinuation of study drug was required for nonserious infection, neutrophil count 500 cells/mm3 to <1000 cells/mm3, platelet count 25,000 to <75,000 cells/mm3, and use of a central venous dialysis catheter. Permanent discontinuation of study drug was required for serious infection, neutrophil count <500 cells/mm3, platelet count <25,000 cells/mm3, allergy to study drug, new malignancy, or initiation of immunosuppressive therapy. Safety was assessed through monitoring of adverse events throughout the 24-week treatment period and the 24-week post-treatment follow-up period, with particular attention to prespecified adverse events of interest that included infections, cytopenias, and hypersensitivity reactions. Tolerability was assessed by the need for study drug discontinuation due to a drug-related indication. Feasibility of a subsequent larger trial was assessed by recruitment, retention, and adherence to the study drug administration schedule. The primary measure of efficacy was the change in the concentration of hsCRP, a pharmacodynamic marker of IL-1 inhibition, over the 24-week treatment period. Secondary efficacy outcomes included additional circulating markers of inflammation, patient-reported outcomes, and hand-grip strength. Patient-reported outcomes were ascertained centrally at the University of New Mexico using computer-assisted telephone interviewing (Supplementary Table S1). Blood was collected before dialysis at 2 screening visits, the baseline visit, and follow-up visits every 4 weeks. Serum and ethylenediamine tetraacetic acid–treated plasma were stored at −80 °C in 500 μl aliquots for batched measurements. For eligibility determination, the 2 hsCRP measurements were performed in real time at the local laboratories affiliated with the enrolling sites. Aliquots of plasma from the screening visits, as well as the baseline and follow-up visits, were stored for subsequent batched measurements of hsCRP performed at the University of Colorado-Denver using a nephelometric assay (Siemens). For outcome determination, the baseline hsCRP value was derived from the average of the central laboratory measurements from the 2 screening samples and the baseline sample. The central laboratory determined plasma concentrations of IL-6, IL-10, IL-1β, and tumor necrosis factor-α using multiplex enzyme-linked immunoassay assays (Quanterix) performed in duplicate, and serum concentrations of albumin using an enzymatic assay (Beckman Coulter). All measurements on batched samples were performed in duplicate. White blood cells and platelets were quantified at local clinical laboratories in real time for safety monitoring. Eight participants at the Vanderbilt site participated in a pharmacokinetic study in which blood was collected at the following times: (i) start of dialysis on day 1 of study drug administration, (ii) end of dialysis on day 1 of study drug administration, (iii) approximately 24 hours after sample 1, (iv) start of dialysis on day 2 of study drug administration (approximately 48 hours after sample 1), and (v) end of dialysis on day 2 of study drug administration. The same sampling schedule was implemented at week 4. Ethylenediamine tetraacetic acid–treated plasma was stored at −80 °C in 500 μl aliquots for the measurement of anakinra concentrations that was performed at Vanderbilt University Medical Center from batched samples using an enzyme-linked immunoassay assay (R&D Systems). The primary analyses were based on intention-to-treat populations with all participants analyzed based on the randomized group assignment. On-treatment analyses that included participants who had received study drug (anakinra or placebo) within 3 days before blood collection were performed as sensitivity analyses for efficacy outcomes. Study drug exposure was determined from records documenting each administration of study drug. Outcomes are presented as mean and standard deviation for normally distributed values, median and 25th–75th percentile for non-normally distributed values, number and percent, or event rate. P values for comparisons between the anakinra and placebo groups on efficacy endpoints measured repeatedly were determined using linear mixed-effects models with adjustment for fixed effects of the stratification factors (diabetes and enrolling center) and random intercepts of participants. Generalized linear models, with adjustment for fixed effects of the stratification factors, were used with Poisson distribution for events that can occur repeatedly, binomial distribution for binary and incidence measures, and Gaussian distribution for continuous measures. Given the pilot nature of the study with a focus on safety, no corrections were made for multiple comparisons. All analyses were performed using SAS version 9.4 (SAS Institute Inc.) and lme4 packages in R version 4.0.2 (https://www.r-project.org). From a prior preliminary study, we assumed a mean hsCRP at baseline of 9.5 ± 4 mg/l and log-transformed mean hsCRP at baseline of 2.14 ± 0.55 log(mg/l).16Hung A.M. Ellis C.D. Shintani A. et al.IL-1beta receptor antagonist reduces inflammation in hemodialysis patients.J Am Soc Nephrol. 2011; 22: 437-442Crossref PubMed Scopus (98) Google Scholar We selected a sample size of 80 participants (40 patient per arm) with the expectation that it would provide 80% power to detect an effect size of 0.6 SD (equivalent to 0.33 log(mg/l)) difference between treatment arms in the change from baseline to week 24 in log-transformed hsCRP assuming a correlation of 0.6 between pre- and post-treatment hsCRP in the placebo group, and a withdrawal rate of 10% by the end of the 24-week treatment period. The assumption for the hsCRP correlation was based on a study of 50 healthy men and on data from a cohort of 128 hemodialysis patients with monthly hsCRP measurements.17Platz E.A. Sutcliffe S. De Marzo A.M. et al.Intra-individual variation in serum C-reactive protein over 4 years: an implication for epidemiologic studies.Cancer Causes Control. 2010; 21: 847-851Crossref PubMed Scopus (33) Google Scholar,18Hung A. Pupim L. Yu C. et al.Determinants of C-reactive protein in chronic hemodialysis patients: relevance of dialysis catheter utilization.Hemodial Int. 2008; 12: 236-243Crossref PubMed Scopus (46) Google Scholar Between December 6, 2017, and October 1, 2019, 176 patients provided informed consent for the trial and underwent eligibility screening (Figure 1). Eighty patients met the eligibility criteria and were randomized to anakinra (N = 38) or placebo (N = 42). The most frequent reasons for ineligibility were an absolute neutrophil count <2500 cells/mm3 or at least 1 of the 2 screening hsCRP values below the required threshold. The baseline characteristics were similar across randomized groups except for a slightly higher age among participants randomized to anakinra (59.6 ± 10 vs. 54.1 ± 13.5 years; Table 1). The majority of participants (58.8%) were Black, and the median duration of treatment with dialysis was 4.4 years (25th–95th percentile: 1.9–7.2 years). Because of the emerging COVID-19 pandemic, a decision was made to stop administering study drug on March 13, 2020, at which time 3 participants had 1–3 doses of study drug that had not yet been administered; all other participants had completed the 24-week treatment period. Follow-up for the trial ended on September 8, 2020. All randomized participants were included in the safety analyses. For the primary analyses exploring efficacy, 1 participant randomized to placebo was excluded because there were no follow-up hsCRP measurements.Table 1Baseline characteristicsCharacteristicAll (N = 80)Anakinra (N = 38)Placebo (N = 42)Age, yr56.7 (12.2)59.6 (10.0)54.1 (13.5)Black, n (%)47 (58.8)23 (60.5)24 (57.1)White, n (%)24 (30.0)10 (26.3)14 (33.3)Asian, n (%)3 (3.8)2 (5.3)1 (2.4)Hispanic/Latino, n (%)8 (10.0)5 (13.2)3 (7.1)BMI, kg/m233.2 (8.1)33.7 (8.6)32.8 (7.7)Predialysis systolic BP, mm Hg145.0 (23.6)145.1 (23.4)144.9 (24.1)Predialysis diastolic BP, mm Hg77.8 (17.6)77.9 (15.6)77.7 (19.4)Hypertension, n (%)72 (90.0)34 (89.5)38 (90.5)Diabetes mellitus, n (%)45 (56.2)22 (57.9)23 (54.8)Coronary artery disease, n (%)24 (30.0)11 (28.9)13 (31.0)Congestive heart failure, n (%)20 (25.0)9 (23.7)11 (26.2)Hyperlipidemia, n (%)37 (46.2)20 (52.6)17 (40.5)Current tobacco use, n (%)6 (7.5)4 (10.5)2 (4.8)AV fistula, n (%)67 (83.8)31 (81.6)36 (85.7)AV graft, n (%)13 (16.2)7 (18.4)6 (14.3)Dialysis vintage, yr4.43 (1.85–7.23)4.32 (1.74–6.50)4.56 (2.10–7.67)Dialysis <1 yr, n (%)14 (17.5)6 (15.8)8 (19.0)Single pool Kt/V1.5 (0.2)1.6 (0.2)1.5 (0.2)Statin use, n (%)33 (41.2)17 (44.7)16 (38.1)Antiplatelet agent use, n (%)40 (50.0)22 (57.9)18 (42.9)Hemoglobin, g/dl11.0 (10.5–11.8)11.3 (10.5–12.2)10.7 (10.3–11.6)White blood cells, ×109/l6.9 (6.2–8.0)6.8 (6.3–7.5)6.9 (6.1–8.4)Neutrophils, ×109/l4.45 (3.52–5.45)4.41 (3.66–5.12)4.55 (3.51–5.59)Platelets, ×109/l224.5 (187.9–281.5)225.5 (199.2–261.4)222.8 (180.0–282.5)Creatinine, mg/dl9.3 (7.7–11.6)9.3 (7.5–10.9)9.4 (8.0–11.7)Albumin, g/dl3.9 (0.3)3.9 (0.3)3.9 (0.2)hsCRP, mg/lahsCRP value is the average of values from the screening 1, screening 2, and baseline visits from the batched measurements performed by the central laboratory. If all 3 samples (screening 1, screening 2, and baseline) were not available for the centralized measurements, the average of the available samples was used.7.2 (5.4–16.0)7.2 (5.4–15.8)bFor 35 participants, the average was based on 3 measurements, for 2 participants the average was based on 2 measurements, and for 1 participant the average was based on 1 measurement.7.2 (5.8–16.0)cFor 33 participants, the average was based on 3 measurements, for 5 participants the average was based on 2 measurements, and for 4 participants the average was based on 1 measurement. Values shown are mean (SD) or median (25th–75th percentile) unless otherwise indicated.AV, arteriovenous; BMI, body mass index; BP, blood pressure; hsCRP, high-sensitivity C-reactive protein; No., number.a hsCRP value is the average of values from the screening 1, screening 2, and baseline visits from the batched measurements performed by the central laboratory. If all 3 samples (screening 1, screening 2, and baseline) were not available for the centralized measurements, the average of the available samples was used.b For 35 participants, the average was based on 3 measurements, for 2 participants the average was based on 2 measurements, and for 1 participant the average was based on 1 measurement.c For 33 participants, the average was based on 3 measurements, for 5 participants the average was based on 2 measurements, and for 4 participants the average was based on 1 measurement.Values shown are mean (SD) or median (25th–75th percentile) unless otherwise indicated. Open table in a new tab AV, arteriovenous; BMI, body mass index; BP, blood pressure; hsCRP, high-sensitivity C-reactive protein; No., number. Participant retention and study drug exposure are shown in Table 2. Eight participants (21.1%) in the anakinra group and 8 (19.0%) in the placebo group withdrew from the trial; 5 of the withdrawals in the anakinra group and 4 of the withdrawals in the placebo group occurred during the 24-week treatment period (Figure 2). The most common reasons for withdrawal were death (N = 6) and kidney transplantation (N = 6). Study drug was permanently discontinued for 12 participants (31.6%) in the anakinra group and 11 participants (26.2%) in the placebo group (Table 2 and Figure 3). The most frequent reason for study drug discontinuation was a decision by the participant (N = 5 in the anakinra group; N = 3 in the placebo group) without a medical indication for stopping study drug. Study drug was permanently discontinued for a medical reason (infection, cytopenia, use of a prohibited medication, placement of a central venous catheter, or kidney transplantation) by 4 participants in the anakinra group and 5 participants in the placebo group. Study drug exposure was 71.9% of target and 75.5% of target in the anakinra and placebo groups, respectively, with the target defined as administration 3 times per week for the full 24 weeks (Table 2). Administration of expected doses, defined as those administrations that were intended, with administrations during periods of temporary or permanent study drug discontinuation excluded from the denominator, was 94.6% and 94.9% in the anakinra and placebo groups, respectively.Table 2Withdrawal and study drug discontinuationEventAnakinra (N = 38)Placebo (N = 42)P valueWithdrawal from trial, n (%)8 (21.1)8 (19.0)0.7 Kidney transplantation33 Transfer to nonparticipating dialysis unit10 Participant decision10 Investigator decision01 Death24 OtheraOne participant was withdrawn at week 4 of previously unrecognized prerandomization neutrophil count <2500 cells/mm3.10Study drug permanent discontinuation, n (%)12 (31.6)11 (26.2)0.6 Infection11 Central venous dialysis catheter01 Allergy10 Cytopenia10 Kidney transplantation12 Initiation of prohibited medication01 Transfer to nonparticipating dialysis unit20 Participant decision53 Investigator decision11 Other02Study drug temporary discontinuation, n (%)13 (34.2)12 (28.6)0.6% Study drug administration, mean (SD) % of target dosebTarget dose is the total dose that would be administered if a participant remained on study drug for the full 24 weeks and is an indication of exposure to study drug.71.9 (30.7)75.5 (31.8)0.6 % of expected dosecExpected dose is the total dose that should be administered while a participant is being followed and while study drug has not been temporarily or permanently discontinued and is an indication of protocol fidelity.94.6 (10.8)94.9 (8.4)0.9a One participant was withdrawn at week 4 of previously unrecognized prerandomization neutrophil count <2500 cells/mm3.b Target dose is the total dose that would be administered if a participant remained on study drug for the full 24 weeks and is an indication of exposure to study drug.c Expected dose is the total dose that should be administered while a participant is being followed and while study drug has not been temporarily or permanently discontinued and is an indication of protocol fidelity. Open table in a new tab Figure 3Timing of permanent discontinuation of study drug by the treatment group.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Adverse events are summarized in Table 3. The total number of adverse events was 96 in the anakinra group and 129 in the placebo group. For serious adverse events, both the proportion of participants with 1 or more events and the event rates were similar in the anakinra and placebo groups. Six participants died during the trial, 2 in the anakinra group and 4 in placebo group. None of the deaths in either group was thought by the site investigator to be related to study drug. The 2 deaths among participants randomized to anakinra were due to cardiac arrest during a cardiac catheterization procedure at week 8 of anakinra administration and COVID-19 at 25 weeks after discontinuation of study drug.Table 3Adverse events during either the study drug or post-study drug administration periodAnakinra (N = 38)Placebo (N = 42)P value for number of patients w/eventP value for event rateEventPatients w/event, n (%)Events per patient-yearPatients w/event, n (%)Events per patient-yearAny serious adverse event17 (44.7)2.7123 (54.8)2.740.30.6Deaths2 (5.3)0.124 (9.5)0.220.50.5AEs of interest Any AE of interest7 (18.4)0.4811 (26.2)1.400.40.01 InfectionaA single infection adverse event may be categorized under more than 1 type of infection.5 (13.2)0.3611 (26.2)1.400.10.002Nonserious infectionbInfection that did not require hospitalization for >2 days.3 (7.9)0.186 (14.3)0.430.30.1Pneumonia0 (0)04 (9.5)0.380.10.003Bacteremia1 (2.6)0.060 (0)00.50.2Systemic fungal infection0 (0)00 (0)0——CNS infection0 (0)00 (0)0——Infection-associated sepsis0 (0)02 (4.8)0.110.50.1Infection-associated death1 (2.6)0.061 (2.4)0.050.90.9Other serious infection2 (5.3)0.125 (11.9)0.380.20.1 NeutropeniacDefined as absolute neutrophil count <1000/mm3.,dOccurred in participant who was found at week 4 to have been ineligible based on prerandomization neutrophil count.1 (2.6)0.060 (0)00.50.2 ThrombocytopeniaeDefined as platelet count <75,000/mm3.0 (0)00 (0)0—— Hypersensitivity reaction1 (2.6)0.060 (0)00.50.2AE, adverse event.a A single infection adverse event may be categorized under more than 1 type of infection.b Infection that did not require hospitalization for >2 days.c Defined as absolute neutrophil count <1000/mm3.d Occurred in participant who was found at week 4 to have been ineligible based on prerandomization neutrophil count.e Defined as platelet count <75,000/mm3. Open table in a new tab AE, adverse event. The prespecified adverse events of interest are shown in Table 3. The rate of adverse events of interest was lower in the anakinra group (0.48 per patient-year) than in the placebo group (1.40 per patient-year;